After Medscape’s article by Steve Stiles
NEW ORLEANS, LA November 15, 2016 — Early intravenous treatment with a synthetic natriuretic peptide decongested patients with acute decompensated heart failure (ADHF) and made them feel better in the first 48 hours but did nothing to improve long-term survival, in a large randomized trial.
Nor did the drug, ularitide (Cardiorentis), an analogue of native urodilatin, seem to protect the myocardium from damage as measured by troponin levels, which was an important prospective end point in the Trial of Ularitide Efficacy and Safety in Acute Heart Failure (TRUE-AHF).
The study was less a test of ularitide’s decongestive prowess than of an unsubstantiated but respected strategy for treating ADHF in a clinically meaningful way, according Dr Milton Packer (Baylor University Medical Center, Dallas TX), chair of its executive committee.
It measured changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin levels as proxies for changes in ventricular wall stress and ventricular “microinjury,” respectively, during a 48-hour ularitide infusion that effectively decongested the patients. The study then explored whether that early treatment, initiated a median of 6 hours after presentation, would manifest months or years later as reduced cardiovascular mortality, Packer said when presenting TRUE-AHF here at the American Heart Association 2016 Scientific Sessions.
With ularitide, patients achieved cardiac and intravascular decongestion, but in doing so “we did not reduce microinjury or change the natural course of heart failure. That changes the way that we look at acute heart failure and our scientific thinking about his disease,” Packer said at media briefing on the trial.
“There is a hypothesis that somehow if you intervene early in patients with heart failure using something magical for 48 hours, that somehow just giving a drug for 48 hours changes the course of the disease for months and years afterward. That’s true of acute coronary syndromes, but it’s not true of acute heart failure,” Packer observed for heartwire from Medscape.
“Six hours, in these patients, is unbelievable,” he said about the median presentation-to-treatment time. “That’s the shortest time of any trial to date.” But he added, “If we think that reducing wall stress at that point in time makes a long-term difference, we are mistaken.”
Shaking the Early-Intervention Hypothesis
Dr Clyde Yancy (Northwestern University, Chicago, IL) agreed for heartwire that TRUE-AHF has shaken some presumptions about ADHF. “Is it worthwhile to still pursue the early-injury hypothesis? I think a compelling statement can be made that the results of TRUE-AHF really negate the importance of this particular component in our treatment strategy.”
In an interview, he pointed out that the definition of “early intervention” is a bit arbitrary as it refers to treatment soon after presentation with ADHF. But decompensation gets under way “days if not longer” before that.
So, said Yancy, who was not involved in the trial, perhaps “early” interventions could be aimed not at the emergency-department phase, “but at some earlier point before the myocardial injury becomes manifest. That may still be worth exploration, using some other modality to detect the early decompensation.”
TRUE-AHF tested the early-intervention hypothesis, agreed observer Dr Mark Creager (Dartmouth-Hitchcock Medical Center, Lebanon, NH) for heartwire , but specifically with respect to ularitide therapy.
“We need to look very carefully at aggressive intervention early on, certainly when patients first present, and we can improve patient awareness and get them in even earlier to see if that will reduce the risk of events long term. But this particular intervention didn’t address that.”
Creager noted that ularitide indeed makes patients less wet, “but it’s not necessarily affecting afterload. So I think this particular approach, with this particular drug, was not effective, but it does not exclude the possibility or even the probability that more aggressive intervention, early on, in patients who present with acute decompensated heart failure may have long-term benefit.”
But Packer said, “If there is a drug out there that, given for only 48 hours, would affect long-term outcomes, I would tell you it’s not because it’s a vasodilator, its not because it reduces wall stress—it’s because it must have an additional mechanism of action.”
Shaking the Myocardial Microinjury Hypothesis
The study seems to question whether early in-hospital intervention is needed to prevent damage to the ventricular wall from distention, as assessed using the biomarkers, observed Yancy when interviewed.
“What do we really know about this troponin signal in heart-failure decompensation? Is it really an injury signal, or is it a biomarker that reflects something different?” Troponins, he said, might enter the bloodstream due to elevated pressures and ventricular distention for reasons other than myocyte damage.
“I think we can put a question mark on whether the elaboration of troponin equates to microinjury, which in and of itself is a little bit of a presumed attribute or aspect of heart failure,” one that probably hasn’t been definitively tested, according to Yancy.
“Microinjury is a term of convenience that’s not necessarily couched in histopathologic studies,” he said. “I think we need to be a little bit circumspect about that whole microinjury phenomenon and realize there may be another reason why we’re seeing troponin.”
The Effects of Decongestion
TRUE-AHF randomized 2157 mostly white, mostly male patients at 156 centers in North America, South America, and Europe to receive IV ularitide at 15 ng/kg/min or placebo double-blind for 48 hours after presentation with ADHF by traditional clinical, biomarker, and radiographic criteria. About half had coronary artery disease.
As compared with placebo, ularitide was accompanied by significant increases in hemoglobin (P<0.001) and serum creatinine (P=0.005) and decreases in hepatic transaminases (P<0.001), which are expected signs of intravascular decongestion, according to Packer.
The 1088 receiving ularitide and 1069 getting placebo did not differ (P=0.70) in degree of change in high-sensitivity-assay cardiac troponin over 48 hours.
Meeting one of two primary end points, patients who received placebo experienced more episodes of “heart-failure events” in the first 48 hours than did those receiving ularitide (P=0.005).
The hazard ratio (HR) for the second primary end point, cardiovascular mortality, for ularitide vs placebo over a median follow-up of 27 months was 1.03 (95% CI 0.85–1.25, P=0.75).
Nor were there differences between the groups in any of the other prospectively defined secondary end points, which included hospital and ICU lengths of stay, worsening HF in the first 120 hours, 30-day HF-rehospitalization rate, and the composite of death or CV rehospitalization in the first 6 months.
Implications for Serelaxin
Yancy pointed out that in TRUE-AHF, the control group received placebo on top of standard therapy for ADHF but were prohibited from receiving vasodilators or positive inotropic agents. So the trial “may have been a referendum not only on early administration, not only on microinjury, but it could have been a referendum on vasodilator therapy.”
Perhaps one message, he said, is that physicians should be “more circumspect” about vasodilators per se in ADHF, because the trial used them as early intervention to target microinjury and had a null effect on clinical outcomes.
“Now that’s a bigger question, but if that question is correct, it would give me pause to consider ongoing studies that are using vasodilator therapy early,” Yancy said, referring to trials of the vasodilator serelaxin (Novartis), such as RELAX-AHF2, which has a projected enrollment of at least 6500 patients with ADHF.
Its primary outcomes, including CV mortality at 6 months and worsening HF through day 5, are anticipated next year.
In TRUE-AHF, wondered Yancy, “have we seen a signal of what we can expect in the future?”
TRUE-AHF was sponsored by Cardiorentis. Packer discloses that w ithin past 2 years he has been a consultant to Admittance, Amgen, AstraZeneca, Bayer, BioControl, Boehringer Ingelheim, Boston Scientific, Celyad, Cardiorentis, Daiichi Sankyo, GlaxoSmithKline, Novartis, Novo Nordisk, Relypsa, Takeda, and ZS Pharma.